This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A cell reproduces by performing an orderly sequence of events in which it duplicates its contents and then divides in two. This cycle of duplication and division is called the cell cycle. At the end of each cycle, called mitotic phase, duplicated chromosomes must be accurately segregated to daughter cells for faithful transmission of genetic information. Errors in this process cause an abnormal number of chromosomes, a hallmark of human tumor progression. In order to assure accurate chromosome segregation, the mitotic checkpoint is activated to arrest cell cycle progression until errors that would generate a lost chromosome have been fixed. Several proteins are known to have pivotal roles in this on and off checkpoint signaling, although the precise mechanisms remains to be further elucidated. I propose here to pursue several approaches to deciphering mitotic checkpoint signal activation, transduction, silencing, and the consequences of deficits from errors in each of these.